Ultra-long-acting in-situ forming implants with cabotegravir protect female macaques against rectal SHIV infection

Ultra-long-acting delivery platforms for HIV pre-exposure prophylaxis (PrEP) may increase adherence and maximize public health benefit. We report on an injectable, biodegradable, and removable in-situ forming implant (ISFI) that is administered subcutaneously and can release the integrase inhibitor cabotegravir (CAB) above protective benchmarks for more than 6 months. CAB ISFIs are well-tolerated in female mice and female macaques showing no signs of toxicity or chronic inflammation. In macaques, median plasma CAB concentrations exceed established PrEP protection benchmarks within 3 weeks and confer complete protection against repeated rectal SHIV challenges. Implant removal via a small incision in 2 macaques at week 12 results in a 7- to 48-fold decrease in plasma CAB levels within 72 hours. Modeling to translate CAB ISFI dosing suggests that a 3 mL injection would exceed protective benchmarks in humans for over 5 months post administration. Our results support the clinical advancement of CAB ISFIs for ultra-long-acting PrEP in humans.

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All studies must disclose on these points even when the disclosure is negative. Reporting for specific materials, systems and methods The data underlying Fig. 1a,b,c, Fig 2a, Fig 3e, Fig 7b-d as well as Supplementary Fig. 1a,b,c, and Supplementary Fig. 2a-b are available in the associated source data file. All other supporting the findings of this manuscript are available from the corresponding authors (J.G.G.L and S.R.B) upon reasonable request.
The number of macaques and mice per group was selected to account for potential variability in drug metabolism which may be due, but not limited, to differences in age, and weight. We did not conduct a power analysis to determine group sizes for the PK and efficacy studies No samples or animals were excluded from analysis.
All in vitro studies had n=3 replicates. In vivo mouse pharmacokinetic studies had n=6 mice and in vivo mouse safety studies had n=3 mice per time point. Macaque PK studies had n=3 macaques, efficacy studies had n=4 challenged macaques (n=2 CAB ISFI treated macaques challenged between 4-8 weeks and n=2 CAB ISFI treated macaques challenged between 14-18 weeks with n=1 untreated macaque as the control), and safety studies had n=6 CAB ISFI treated macaques for Draize scale analysis and n=3 CAB ISFI treated macaques and n=1 untreated macaque as a control for histology results. All n's in these experiments had produced similar results suggesting successful replication and reproducibility.
No randomization was used to determine how samples/animals were allocated to experimental groups. Mice were allocated to each experimental group. Each experimental group had animals with similar age and weight. Method section/pg 36-38. Macaques in the study groups were not randomly assigned as we generally try to maintain social pairs with appropriate cage separation (G2 panels to allow limited physical/visual interactions) throughout the study. However, the average age and weights were similar between the groups. Methods section pg 41 line 828 Blinding was used to analyze histology samples to determine inflammation scores. The board-certified pathologist was given numbered samples, but not the allocation of the samples to treatment groups. Samples from control mice and macaques (no treatment, baseline inflammation score) were unblinded to the pathologist. Methods section/pg 36-37 and 41-42. Blinding was not relevant in the treated macaques as they were all receiving the same dose of CAB ISFI. Blinding was not relevant for mice PK studies as they were all receiving the same dose of CAB ISFI. Blinding was not relevant for in vitro studies as we had to track the individual CAB release of each implant in vitro for accurate results (n=3).